1. David A. Hovda, Ph.D. Director, UCLA Brain Injury Research Center Professor of Neurosurgery Molecular and Medical Pharmacology David Geffen School of Medicine at UCLA WWW.BIRC.UCLA.EDU 2011 National Neurotrauma Conference Hollywood Beach, FL July 13, 2011 Mechanisms of Concussion Funded by: NS02197, NS27544, NS052406 UC Neurotrauma Initiative, UCLA Faculty Grant Program and the Lind Lawrence Foundation. NOTHING TO DISCLOSE

3. EVERY TBI STARTS OUT AS A CONCUSSION What is so mild about mild traumatic brain injury? Walker, A.E et al, 1944; The physiological basis of concussion. J. Neurosurgery, 1: 103-166

4. Constantin van Monakow 1853-1930 Swiss Neurologist of Russian Extraction Diaschisis To distinguish between the transient central nervous disorders due to suppression of brain activity and the deficits resulting from brain lesions that never disappear.

5. Adenosine Triphosphate (ATP) 116 Watts/Hour

6. SAGITTAL HEAD AND BRAIN MOTION Dr. Gennarelli Dr. Gurdjian

7. Neurometabolic Cascade: Potassium & Glutamate Flux Katayama , et.al., J Neurosurg 1990 K+ K+ K+ K+ K+ Glutamate Glutamate

8. Neurometabolic Cascade: Hyperglycolysis and Energy Crisis K+ Pump Energy Crisis!!! ADP ATP Glucose ATP ADP Glutamate Glutamate

9. Neurometabolic Cascade: Calcium, mitochondrial dysfunction and death ATP Glucose Energy Crisis!!! Mito Cell Damage/ Death!!! ATP For review, see Giza and Hovda, J Athl Training, 2001 Ca2+ Protease activation Glutamate Glutamate

10. Neurometabolic Cascade: Axonal Injury Axonal swelling Myelin Damage Axonal blebs and swelling Microtubule and neurofilament injury Impaired axonal transport Axonal degeneration Ca2+ Inflammation Glutamate

11. Neurometabolic Cascade: Now we can see it Energy Crisis Mito PET, MRS Protein Biomarkers? Cell Damage/ Death Protease activation MRI Axonal injury DTI Altered neurotrans-mission Glutamate fMRI

12. McAllister, et al. Neurology, 1999 Human mTBI: Impaired Activation (fMRI) Mildly injured individuals demonstrate abnormal activation patterns during a more difficult working memory task. Mild TBI patients (GCS 13-15), n=12; controls n=11 Average time of testing was 22.1 ± 10.5 days after TBI. Loss of consciousness: 1 to 30 min. Post-traumatic amnesia: 15 min to 24 hrs. % correct mTBI control 0-back 95.1 96.2 1-back 95.8 95.5 2-back 81.0 89.4 No significant differences Mild TBIs Controls

13. Human mTBI: Abnormal axons (DTI) Wilde E, et.al. Neurology, 2008 In adolescents with mTBI, DTI of the CC performed within 6 days showed increased FA and decreased diffusivity. These abnormalities in DTI correlated well with post-concussion symptoms.

15. CMRglc CBF CMRO 2 OEF

16. TBI as a Metabolic Disorder: Clinical Studies Acute Hyperglycolysis Bergsneider et al., 1997 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 Months Post-injury 0 1 2 3 4 5 6 7 8 9 10 0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 Days Post-injury Cortical CMRglc Chronic Metabolic Depression 1st PET 2nd PET

17. Human mTBI: Altered metabolism (MRS) Vagnozzi, et.al. Neurosurgery, 2008 Single concussion Double concussion There were significant reductions of NAA/Cr for 30 days after 1 concussion and 45 days after 2 concussions. Vagnozzi, et.al. Brain, 2010

18. GLUCOSE GLUCOSE LACTATE LACTATE C P C M C E G-6-P BBB brain capillary endothelial cytoplasm PYRUVATE PYRUVATE ACETYL-CoA TCA CO 2 H 2 O k 1 k 3 k 2 Pentose Shunt GLYCOGEN GLYCOGEN – ~97% ~13% Amino Acids ~5% GLUCOSE G-6-P G-1-P PYRUVATE LACTATE hexokinase ASTROCYTE NEURON 2 ATPs 36 ATPs Oxygen/ Glucose Ratio 1 Glucose:5.6 parts Oxygen 5.6 Oxygen G1 G1 G3 G1 G1 G1 G1 MCT MCT MCT MCT MCT hexokinase glucose-6- phosphatase

19. Molar Oxygen-to-Glucose Ratio (OGR): Normal ~ 5.6 CMRO2 CMRglc CMRO 2 OGR Image Processing Low OGR High OGR

20. Lactate Uptake Occurs Frequently During the Post-Acute Phase Uptake Release Trauma Normal Post-Injury Day % Positive CMRlac 0 65.2% 1 58.1% 2 39.0% 3 40.5% 4 43.9% 5 20.0%

21. Glucose Lactate Glucose Lactate Probe 1 Probe 2

22. Metabolic Priorities After Traumatic Brain Injury The role for Glucose and Lactate had Changed! Astrocytes may need help! Bartnik et al. J Neurotrauma 2005, 2007a,b Dusick et al. J Cereb Blood Flow Metab 2007

24. TBI– Induced Hyperglycemia Vespa et al. Crit Care Med 2006 Start of insulin infusion

25. Intensive Insulin Treatment is Associated with Increased Microdialysis Markers of Injury Vespa et al Crit Care Med 2006

26. Tight Glycemic Control may be Associated with Increased Oxygen Extraction

28. The UCLA Brain Injury Research Center Basic Scientists Chris Giza, M.D. Fernando Gomez-Pinilla, Ph.D. Grace Griesbach, Ph.D. Neil Harris, Ph.D. Mayumi Prins, Ph.D. Richard Sutton, Ph.D. Graduate Students Gretchen Miller. Maxine Reger Naomi Santa Maria Derek Verley Lab Assistants Yan Cai, M.S. Sima Ghavim Nurses Maria Etchepare Sue Yudovin Clinical Investigators Thomas Glenn, Ph.D. Neil Martin, M.D. Paul Vespa, M.D. Marvin Bergsneider, M.D Robert Asarnow, M.D. Andy Madikians, M.D. David McArthur, Ph.D M.P.H. Michelle van Hirtum-Das, M.D. Talin Babikian, Ph.D. Funded by: NS02197, NS27544, NS052406 UC Neurotrauma Initiative, UCLA Faculty Grant Program and the Lind Lawrence Foundation. www.birc.ucla.edu Post Doctoral Fellows Sarah Copeland, M.D. Ph.D. Nobouhiro Moro, M.D., Ph.D Katsunori Shijo, M.D., Ph.D.

29. Thank You!